P1-235 CLAC-positive senile plaques in Alzheimer brains: mutually exclusive distribution to Aβ40 and acquisition of protease resistance

Kowa, Hisatomo; Sakakura, Tomoko; Matsuura, Yusuke; Wakabayashi, Tomoko; Tsuji, Shoji; Mann, David; Hashimoto, Tadafumi; Iwatsubo, Takeshi

doi:10.1016/s0197-4580(04)80548-7

Cited by 2 publications

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“…2C). Our findings offer an explanation for the increased protease resistance of CLAC positive plaques [13]. Therefore, we speculate that CLAC assembles Aβ fibrils into protease‐resistant aggregates in vivo and thereby obstructs the clearance of amyloid.…”

Section: Resultsmentioning

confidence: 68%

Collagenous Alzheimer amyloid plaque component assembles amyloid fibrils into protease resistant aggregates

Söderberg¹,

Dahlqvist²,

Kakuyama³

et al. 2005

The FEBS Journal

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Alzheimer's disease (AD) is characterized by amyloid deposits of the amyloid b-peptide (Ab) in brain [1]. Ab is a 40-42 amino acid peptide that is proteolytically derived from the b-amyloid precursor protein (APP). The longer Ab42 variant aggregates more rapidly than the more abundant Ab40 [2] and is the species deposited initially in the brain in AD and Down's syndrome [3]. Several lines of evidence suggest that APP processing and Ab levels have a central role in the pathogenesis of AD. The APP gene is located on chromosome 21 (which is present in triplicate in Down's syndrome), providing an explanation for the elevated levels of APP and Ab, as well as for the AD-like pathology, observed in Down's syndrome. Moreover, mutations in genes linked to familiar early onset AD generally result in altered APP processing and an increased Ab42 ⁄ Ab40 ratio [4].It is not known how the amyloid plaques are formed. In vitro studies indicate that unstructured Ab monomers spontaneously form soluble oligomers (seeds), which, in turn, form protofibrils and mature fibrils. Other molecules could be of importance for the polymerization process in vivo, including apolipoproteins E

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Section: Resultsmentioning

confidence: 68%

Collagenous Alzheimer amyloid plaque component assembles amyloid fibrils into protease resistant aggregates

Söderberg¹,

Dahlqvist²,

Kakuyama³

et al. 2005

The FEBS Journal

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“…For example, collagens harboring triple-helix structure are known to be resistant against conventional proteinases, suggesting that CLAC deposited in senile plaques may confer amyloid deposits resistance to proteolytic degradation or microglial phagocytosis. Indeed, we have shown that A␤ immunoreactivities in CLAC-positive senile plaques are more resistant to proteinase K digestion compared with those in CLACnegative ones (33). Considering the discrepancies in the effects of apoE on A␤ fibrillization and deposition that were previously documented in vitro (inhibitory (13,14)) and in vivo (promoting (12)), however, further in vivo studies, especially cross-breeding experiments of transgenic mice overexpressing ␤APP and CLAC-P, will be mandatory.…”

Section: Discussionmentioning

confidence: 91%

CLAC Binds to Amyloid β Peptides through the Positively Charged Amino Acid Cluster within the Collagenous Domain 1 and Inhibits Formation of Amyloid Fibrils

Osada¹,

Hashimoto²,

Nishimura³

et al. 2005

Journal of Biological Chemistry

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CLAC (collagenous Alzheimer amyloid plaque component) is a proteolytic fragment derived from a novel membrane-bound collagen, CLAC-P/collagen type XXV, that deposits in senile plaques associated with amyloid ␤ peptides (A␤) in the brains of patients with Alzheimer's disease. We previously showed that CLAC binds to the fibrillized form of A␤ in vitro, although the mechanism and the subdomains that mediate interaction of CLAC with A␤ as well as the effect of binding of CLAC on amyloid fibril formation remain unknown. Here we show that the collagenous domain 1 of CLAC, which is rich in positively charged amino acid residues, mediates its interaction with A␤ and that this binding is mediated by an electrostatic interaction and requires formation of the triple helix structure of CLAC. The soluble form of CLAC purified from the media of cells transfected with CLAC-P inhibited fibrillization of A␤ in vitro, especially in its elongation phase. These results suggest the antiamyloidogenic roles of CLAC in the pathophysiology of Alzheimer's disease.Alzheimer's disease (AD) 1 is an elderly onset neurodegenerative disease causing dementia that is pathologically characterized by a massive accumulation of amyloid deposits in senile plaques or cerebrovasculature and of tau-rich neurofibrillary lesions (1). The principal component of the amyloid deposits is amyloid ␤ peptide (A␤), which is proteolytically produced from a transmembrane precursor, ␤APP, as 38 -43-amino acid fragments (2, 3). A␤ secreted from cells exhibits a heterogeneity in its C-terminal extent; A␤42 ending at the 42nd residue, which comprises ϳ10% of A␤40 in total secreted A␤, aggregates much faster than A␤40 (4) and deposits initially as diffuse-type plaques in AD or Down's syndrome brains (5). Moreover, missense mutations in ␤APP, presenilin 1 and presenilin 2 genes linked to early onset familial AD increase the production of A␤42 (6 -8). These findings collectively suggest that aggregation and deposition of A␤ are closely linked to the pathogenesis of AD.A number of non-A␤ proteinaceous components, e.g. apolipoprotein E (apoE), ␣1-antichymotrypsin, ␣ 2 -macroglobulin, complement component C1q, amyloid P component, have been identified associated with senile plaque amyloids (9), some of which have been shown to affect fibrillization of A␤ (10). Genetic polymorphism of apoE, especially the ⑀4 genotype, is known as the major genetic risk factor of AD (11), and accumulating evidence from experimental studies suggests that apoE may affect the fibrillization and deposition of A␤, thereby leading to AD; ablation of apoE gene reduced A␤ deposition in transgenic mice overexpressing human ␤APP, whereas further transgenic supplementation of human apoE ⑀4 gene accelerated deposition of ␤-sheet-rich A␤ (12). In vitro studies, however, showed that apoE also has an inhibitory effect on fibrillization of A␤ (13,14), implicating apoE in various aspects of ␤-amyloid formation in AD. These previous results emphasize the compelling need for the analysis of effects of other no...

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P1-235 CLAC-positive senile plaques in Alzheimer brains: mutually exclusive distribution to Aβ40 and acquisition of protease resistance

Cited by 2 publications

References 0 publications

Collagenous Alzheimer amyloid plaque component assembles amyloid fibrils into protease resistant aggregates

Collagenous Alzheimer amyloid plaque component assembles amyloid fibrils into protease resistant aggregates

CLAC Binds to Amyloid β Peptides through the Positively Charged Amino Acid Cluster within the Collagenous Domain 1 and Inhibits Formation of Amyloid Fibrils

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